Parallel cell processing method and facility

ABSTRACT

The present invention provides improved methods, facilities and systems for parallel processing of biological cellular samples in an efficient and scalable manner. The invention enables parallel processing of biological cellular samples, such as patient samples, in a space and time efficient fashion. The methods, facilities and systems of the invention find particular utility in processing patient samples for use in cell therapy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation of U.S. application Ser. No.16/245,924, filed Jan. 11, 2019, allowed, which is a continuation ofU.S. application Ser. No. 15/327,800, filed Jan. 20, 2017, now U.S. Pat.No. 10,184,949, issued Jan. 22, 2019, which claims priority to PCTApplication No. PCT/EP2015/066666, filed Jul. 21, 2015, which claimspriority benefit of U.S. Provisional Application No. 62/026,748, filedJul. 21, 2014 and Great Britain Application No. 1415329.0, filed Aug.29, 2014, each of which is incorporated herein by reference in theirentireties.

BACKGROUND TO THE INVENTION

Cell therapy is a key area of medical advance in the treatment of arange of conditions and diseases including cancer. Autologous celltherapy, the treatment of a patient with the patient's own cells, is anincreasingly used and improving method for combatting cancers, includingmelanoma and leukaemia, which are refractory to conventional drugtreatment. One area of autologous cell therapy, immunotherapy, usesselection and expansion of cells from the patient's own immune system totarget and attack cancer cells, effectively boosting many fold thepatient's immune response to destroy the cancer cells.

To achieve immunotherapy and other forms of cell therapy samples ofcells taken from a patient, typically in the form of a blood sample,must be processed through a complex workflow to isolate, engineer,concentrate and/or expand by culture the cells which will form thetherapeutic material administered back into the patient. Carrying outthe cell processing workflow requires a series of operations performedusing a variety of processing methods, machines and instruments, eachwith a unique role in the overall process. The process may comprisesteps of different duration and complexity requiring varying degrees ofoperator intervention and skill and all operations must be carried outunder sterile conditions to prevent microbial, viral or othercontamination of the patient sample. The process must also be carriedout using means which maintain the integrity of the patient's materialand prevent partial or whole cross-contamination or mixing of patientsamples to prevent a patient receiving a therapeutic preparation whichis not wholly derived from the patient's own cells.

To achieve the sterility and integrity of patient material allprocessing operations are typically performed in a laboratory or cleanroom furnished with equipment, for example laminar air flow cabinets,which allow the material to be manipulated using open containers in asterile environment to minimise the risk of biological or othercontamination from the environment. To prevent mixing of patientmaterials and maintain the integrity of the sample identity theprocessing operations are carried out in separate and isolatedprocessing rooms or units each of which duplicates the equipment andprocesses of the others. Each duplicated unit provides the necessarysterile working environment and is furnished with all of the samplehandling and processing equipment required to process one single patientsample at one time. As each unit is used only for one patient sample ata time, a facility processing many patient samples requires a number ofidentical processing units and therefore duplicates costs of providingspace, services and equipment, such costs scaling linearly with thenumber of patient samples to be processed. These costs are seen as amajor barrier to the further development of cell therapy and theexpansion of use of cell therapy in a larger patient population as theduplicative approach does not provide economies of scale to reducetreatment costs.

In addition to the high setting up and running costs and the high costsof capacity expansion, the duplication of processing units is extremelyinefficient in use of space and equipment. Since each stage of theprocessing workflow takes a different period of time, the overallthroughput of the workflow is determined by the rate limiting step, i.e.the longest step in the process, and therefore most of the resourcesavailable in each duplicated processing unit are underutilised for muchof the time taken to process a sample through the workflow. In a typicalimmunotherapy processing workflow the process of cell expansion, theculture and growth of cells from the thousands of cells isolated from apatient's blood sample to the millions or billions of cells required fora therapeutic dose, may take up to two weeks. In contrast, the cellisolation and concentration steps used at the beginning and end of theworkflow may take only a few minutes or hours. Consequently in thestandard cell processing facility, using duplication of processingunits, a large amount of space and capital equipment used for short termoperations, such as cell isolation, stands idle during the cellexpansion operation.

In addition to the cost and efficiency shortcomings of the standardduplicated unit approach described above, processing samples in alaboratory or clean room using open containers still retains a risk ofbacterial, viral or other contamination of the sample, does not precludeloss of part or all or the patient sample or processed material at anystage in the process due to operator error, and retains the opportunityfor cross-contamination of samples by residual material remaining in theprocessing unit from a previous patient sample or processed material.

What is required is a means to process patient material in a fashionwhich maximises the efficiency of the processing workflow for time andcost allowing the process to be operated for multiple patients witheconomies of scale that enable use of cell therapy in a larger patientpopulation. Such means must retain the fundamental key principles ofpreventing contamination, mixing, loss of identity or other events whichinterfere with the physical and identity integrity of the patient sampleand processed therapeutic material.

These features and benefits are not provided by current cell therapyprocessing facilities and such features and benefits are not describedor suggested by the prior art.

US20030175242 describes systems and methods for manufacturing anddistributing cell therapy products. The methods include establishing acentral processing facility and a plurality of satellite facilitiesadministered under a single license for conducting cell therapy,collecting source material at one of the satellite facilities from afirst subject, transporting the source material from the first subjectand delivering the source material to the central processing facility,processing the material at the central processing facility to produce atherapy product for administration to the same first subject,transporting the therapy product back to the satellite facility andadministering the therapy product to the same first subject.

U.S. Pat. No. 8,656,670 provides a system, workflow and facilities fortissue banks comprising a central access corridor having spaces on bothsides for public and private diagnostic areas, public and private cleanroom areas for processing, culturing and other manufacturing steps andpublic and private storage areas, wherein all public facilities are onone side of the central access way and private facilities are on theother side provided with air locked sample pass through connectionsbetween each area.

WO1998028700 describes a method for quality management in a cell therapyprocess of sampling cells from a patient, specific treatment of thesecells according to a specific treatment protocol, and reinfusion ofcells into the patient. The method comprises steps of identifyingentities involved in the therapeutic process; steps of sequential andconditional validation of the therapeutic process; and steps of qualitycontrol. The steps of identification, validation and control are carriedout for each batch of samples taken from a given patient.

WO2006129312 describes a method for automated cell processing, includingreceiving a tissue sample containing a multiplicity of cells belongingto multiple cell types, and automatically increasing both the proportionof cells of cell type.

WO2007105846 describes a method for using a cell therapy facility and afranchise market business method wherein the facility comprises aplurality of separately prefabricated units having individual-specificfunctions and having an entrance and exit separately partitioned fromeach other so as to minimize occurrence of contamination.

WO2008018671 describes a facility for cell manipulation and cultivationfor production of cell therapy products comprising a room with aL-shaped partition and a clean bench device placed inside the partition,including three clean benches to prevent contamination of cells.

EP1850289 describes the use of RFID (Radio Frequency Identification) inthe workflow of a blood centre and a medical institution from a networkinformation system. In each procedure of the blood collecting and supplyworkflow, the information is read/written by the computer into or froman electronic tag and through the computer information network into theservice management information system.

U.S. Pat. No. 8,099,297 describes a business method and system forordering, purchasing and storing stem cells enabling donors to order andpurchase stem-cells from biological tissue sampled from the donor, suchas, for example, cord-blood stem cells, wherein the ordering processinterfaces directly with attending medical services, and the servicesteps include collection, extraction, preservation, containment,packaging, delivery and storage of the stem cells.

U.S. Pat. No. 8,229,675 provides a method for managing blood productsand tracking their movement in which a database is provided for enteringand storing information pertaining to each patient.

U.S. Pat. No. 8,484,049 describes a system for tissue tracking inmedical facilities. The tissue tracking system may be incorporated witha supply chain, billing, inventory, and/or order systems and may alsotrack environmental conditions of the tissue during reception, storageand issuance.

EP1238671 provides a bank of cord blood cells from which cells may bewithdrawn from storage for both autologous and allogeneic purposes.

EP2263183 relates to a system for the automatic conveyance of biologicalcells for transplant, therapy or research purposes between withdrawalcentres or banks and clinics, transplant centres or research facilitiesand for the monitoring of the processes from request transmission, forsupply of a cell specimen which is suitable for the allogeneictransplant.

U.S. Pat. No. 6,861,954 describes a system for tracking medical productsand for associating medical products with a location based on a RFIDdevice signal.

U.S. Pat. No. 8,005,622 describes a system and method for safelytransfusing blood to a patient in a computerized healthcare environment.A blood product to be administered to a patient is identified and thepatient is identified. A database containing blood compatibility testresults is accessed to determine whether the database contains a bloodcompatibility test result for the identified blood product andidentified patient in order to determine whether the test resultindicates that the identified blood product is compatible for theidentified patient.

U.S. Pat. No. 8,032,306 provides means for identifying a blood productto be administered to a patient by receiving, at a computer at thepatient's bedside, a blood product identifier identifying the bloodproduct to be administered to the patient, identifying the patient byreceiving at the computer a patient identifier and communicating theblood product identifier and the patient identifier to a blood bankdatabase to maintain a record of the blood product administration.

U.S. Pat. No. 8,204,694 describes systems for automatically trackingblood product administration in a computerized healthcare environment.Information regarding a blood product unit received by the blood bankdepartment is documented in a database. An indication that the bloodproduct unit has been administered to the patient by a healthcareprovider is received and the database is automatically updated toreflect that the blood product unit has been administered to thepatient.

U.S. Pat. No. 8,666,762 provides a tissue management system for handlingtissues such as human cells where the tissue management tracking systemprompts and verifies that staff of a medical establishment have handledand used tissue materials in a safe manner.

US20050184153 describes an apparatus for implementing blood samplecollection, blood unit requesting, and blood unit transfusion to apatient, comprising a caregiver identity means carrying anelectronically readable caregiver code, a patient identificationwristband carrying an electronically readable patient code, a readerwherein said reader is capable of reading said caregiver code and saidpatient code.

US20080189045 provides a method for the collection and distribution ofcord blood stem cells using a single collection and distribution entitythat applies a uniform protocol to obtain cord blood stem cell samplesat each of a plurality of different collection facilities enabling agreater number of samples for both private and public cord blood stemcell banks to be obtained.

US20090299763 describes a method for conducting a stem cell technologybusiness such as a regenerative medicine business using inducedpluripotent stem cells (iPSC) and cells differentiated from iPSC wherethe method provides a database of iPSC-derived cells and methods ofusing the database for tracking customers and samples.

US20100049542 describes a blood component collection facility comprisinga plurality of separately operable blood component collectioninstruments and a system for networking the blood component collectionfacility. The networking system provides a system computer linked to aplurality of input devices for tracking donors, operators and bloodcomponent collection instruments with respect to one or more bloodproduct collection procedures. The system computer is linked to at leastone administrative level computing device to monitor blood componentcollection activities throughout the blood component collection facilityand to facilitate decision making on allocation of donors, operator, andblood component collection instruments.

US20130018356 describes a method for characterizing, preparing, usingand disposing of medical equipment such as syringes which are encodedwith unique numbers wherein data characterizing a medication containeris received from a medication device within a clinical workflow andthereafter, one or more data records are generated, modified or appendedto include a portion of the received data.

None of the preceding prior art addresses the problem of optimisingprocessing of biological cellular samples, for example patient samples,in a scalable fashion which provide economies of scale. The presentinvention addresses this problem and provides improved methods andfacilities which can be used to process biological cellular samples suchas patient samples in an efficient and scalable manner.

SUMMARY OF THE INVENTION

According to a first aspect of the present invention there is provided amethod for parallel processing of a plurality of biological cellularsamples comprising

-   -   i) transferring a plurality of cellular samples (S1 to Sn) to a        first processing unit (U1) containing a plurality of identical        processing stations (P1/1 to P1/n);    -   ii) processing each of said cellular samples (S1 to Sn) on a        processing station (P1/1 to P1/n) to produce a plurality of        processed cellular samples (S1/1 to Sn/1);    -   iii) transferring said processed cellular samples (S1/1 to Sn/1)        to a second processing unit (U2) containing a plurality of        identical processing stations (P2/1 to P2/n);    -   iv) processing each of said cellular samples (S1/1 to Sn/1) on a        processing station (P2/1 to P2/n) to produce a plurality of        processed cellular samples (S1/2 to Sn/2); and    -   v) transferring to and further processing said plurality of        processed cellular samples on one or more processing units (UN)        to produce a plurality of processed cellular samples (S1/N to        Sn/N).

Having identical processing stations in a unit allows optimisation ofthe space and services, use of environmental conditions and improvesefficiency of processing.

In one aspect, a unit for long duration processes contains moreprocessing stations than a unit for short duration processes. Thisoptimises space usage, reduces capital equipment costs by avoiding theneed for additional units, and additionally overcomes any bottlenecks inthe processing procedure.

In another aspect, each cellular sample (S1 to Sn) is uniquelyidentifiable.

In a further aspect, each cellular sample (S1 to Sn) is enclosed in acontainer, which container is uniquely identifiable. Preferably thecontainer is sterile.

In one aspect, each cellular sample comprises human cells.

In another aspect, the cellular samples are selected from the groupconsisting of blood samples, tissue aspirates, tissue biopsies, bonemarrow, adipose tissue and umbilical cord blood.

In a further aspect, the cellular samples are derived from one or morepatients.

In one aspect, the processing of the cellular samples involves one ormore processes selected from the group consisting of cell isolation,cell concentration, cell culture, cell expansion, cell transduction andcell formulation.

In another aspect, the method of the invention additionally comprisesthe step of storing the processed cellular samples (S1/N to Sn/N) in acell bank.

In a further aspect, the method is an automated method. For example, themethod may be carried out using robotic arms under the control ofsoftware.

In one aspect, the method additionally comprises the step ofadministering one or more of the processed cellular samples (S1/N toSn/N) to one or more patients.

In another aspect, the one or more patients are the original donors ofthe cellular samples (S1 to Sn). This would be an example of autologouscell therapy.

In a further aspect, the one or more patients are not the originaldonors of the cellular sample (S1 to Sn). This would be an example ofallogeneic cell therapy.

In a preferred aspect, the patient is a cancer patient.

According to a second aspect of the present invention, there is provideda processed cellular sample produced by a method as hereinbeforedescribed.

According to a third aspect of the present invention, there is provideda processed cellular sample as hereinbefore described for use in celltherapy. In one aspect, the processed cellular sample is for use inautologous cell therapy. In another aspect, the processed cellularsample is for use in allogeneic cell therapy.

According to a fourth aspect of the present invention, there is provideda processed cellular sample for use in the treatment of cancer.

According to a fifth aspect of the present invention, there is provideda composition comprising the processed cellular sample as hereinbeforedescribed comprising a biocompatible carrier in a form suitable formammalian administration.

The “biocompatible carrier” is for example a fluid, especially a liquidor a gel, in which the cellular sample can be suspended, such that thecomposition is physiologically tolerable, i.e. can be administered to amammalian body without toxicity or undue discomfort. The biocompatiblecarrier is suitably an injectable carrier liquid such as a sterile,pyrogen-free aqueous solution such as saline (which may advantageouslybe balanced so that the final product for injection is isotonic); anaqueous buffer solution comprising a biocompatible buffering agent (e.g.phosphate buffer); an aqueous solution of one or more tonicity-adjustingsubstances (e.g. salts of plasma cations with biocompatiblecounterions), sugars (e.g. glucose or sucrose), sugar alcohols (e.g.sorbitol or mannitol), glycols (e.g. glycerol), or other non-ionicpolyol materials (e.g. polyethyleneglycols, propylene glycols and thelike). Preferably the biocompatible carrier is pyrogen-free, isotonicsaline or phosphate buffer.

Alternatively, the “biocompatible carrier” may be in the form of amatrix or scaffold which supports the cellular sample. Natural scaffoldsare the total extracellular matrixes of decellularized tissues ororgans. In contrast, biomimetic scaffolds may be composed of naturalmaterials, such as collagen or proteoglycans (proteins with long chainsof carbohydrate), or built from artificial materials, such as metals,ceramics, or polyester polymers.

By the phrase “in a form suitable for mammalian administration” is meanta composition which is sterile, pyrogen-free, lacks compounds whichproduce toxic or adverse effects, and is formulated at a biocompatiblepH (approximately pH 4.0 to 10.5). Such compositions lack particulateswhich could risk causing emboli in vivo, and are formulated so thatprecipitation does not occur on contact with biological fluids (e.g.blood). Such compositions also contain only biologically compatibleexcipients, and are preferably isotonic.

According to a sixth aspect of the present invention, there is provideda cell processing facility for parallel processing of a plurality ofbiological cellular samples comprising a plurality of processing units(U1 to UN) in which each said unit comprises a plurality of identicalprocessing stations (P1/1 to PN/n) for carrying out a specific process,said processing stations performing a different process in each saidunit, wherein the number of processing stations in any one processingunit is varied to optimise the throughput of the cell processingfacility.

In one aspect, a unit for long duration processes contains moreprocessing stations than a unit for short duration processes.

In another aspect, the processing station carries out a process selectedfrom the group consisting of cell isolation, cell concentration, cellculture, cell expansion, cell transduction and cell formulation

In a further aspect, the cell processing facility additionally comprisesa cell bank.

In one aspect, the cell processing facility is located or housed withina hospital or treatment centre.

In another aspect, the cell processing facility is located or housed ina prefabricated building, vehicle, craft, or container for deployment toa location for processing cellular samples and/or cell therapymaterials.

In a further aspect, the cell processing facility is located remotelyfrom the site of cell sample collection and/or processed cell sampleadministration.

In one aspect, the cell processing facility is for use in producingcellular samples for cell therapy such as autologous cell therapy orallogeneic cell therapy. In a preferred aspect, the cell processingfacility is for use in producing cellular samples for treating cancerpatients.

According to a seventh aspect of the present invention, there isprovided a system for parallel processing of a plurality of biologicalcellular samples comprising processing a plurality of biologicalcellular samples in a method as hereinbefore described in a cellprocessing facility as hereinbefore described.

According to an eighth aspect of the present invention, there isprovided a computer program product comprising machine instructionsoperable to configure a data processing apparatus to implement themethod as hereinbefore described.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 : Schematic of a unitised parallel processing facilityillustrating the workflow of patient samples and processed materialsthrough discrete workflow units comprising processing stations andprocessing components.

FIG. 2 : Schematic of an identity custody chain for patient sample andprocessed material illustrating means to achieve physical and identityintegrity through the use, tracking and recording of uniquely encodeddisposable components.

FIG. 3 : Schematic of means of maintaining the physical and identityintegrity of sample and processed material illustrating means to achieveconnection of disposable closed processing components preventing mixing,loss or contamination of sample or processed material through use ofencoded connectors.

FIG. 4 : Schematic of means of providing processing instructions to aprocessing station from an instruction store.

FIG. 5 : Schematic of means of providing processing instructions to aprocessing station from a processing component.

DETAILED DESCRIPTION OF THE INVENTION

A scalable cell therapy facility comprises a number of discreteprocessing units (UNIT 1 to UNIT N) isolated from one another byphysical walls, barriers or other demarcation. Each processing unitcomprises a number of identical processing stations (P1/1 to P1/n inUNIT 1; P2/1 to P2/n in Unit 2; PN/1 to PN/n in UNIT N) appropriate forthe unique processing operation to be carried out within the unit.Patient samples (S1 to Sn) are received by UNIT 1 in uniquely encodedclosed sample containers and processed on processing stations P1/1 toP1/n using a separate uniquely coded closed disposable processingcomponent 1 for each sample. Processed samples in closed componentsappropriate to the workflow stage are sequentially passed through UNIT 2to UNIT N to complete the processing workflow using uniquely codedclosed processing components 2 to N at each stage. At each stage ofprocessing transfer of processed patient material from component tocomponent is tracked by recording component unique identitiesmaintaining an identity custody chain.

UNIT 1 to UNIT N may comprise physically separated rooms or zones withina facility with the operations of processing platforms and handling andtransfer of components and samples being carried out by one or moreoperating staff. Alternatively UNIT 1 to UNIT N may comprise designatedareas within a larger area or room where processing platforms operateautomatically and transfer of components and samples is performed by oneor more robot devices. The facility comprising UNIT 1 to UNIT N may behoused within a larger facility, such as a hospital or other treatmentcentre, or may be a self-contained unit capable of independentoperation. The facility may be housed in a prefabricated building,vehicle, craft, vessel or other container suitable for deployment to asuitable location for processing cell therapy materials. The facilitymay be situated locally or remotely to patients providing samples and/orundergoing treatment. Where the facility is located remotely to patientsampling and/or patient treatment locations patient samples and/or finaltherapeutic materials are transported from and/or to patients in sealeduniquely encoded containers and remote location(s) are connected to thefacility by means to allow transmission and receipt of patient andsample identities to provide means to maintain physical and identityintegrity for samples and processed materials.

The parallel processing facility maintains physical separation ofsamples within the processing units by use of disposable closedprocessing components at all stages in the processing work flow fromsample receipt to formulation of the therapeutic material foradministration. The facility is readily scalable by increasing thenumber of processing stations in each unit and the numbers of processingstations in each unit may be tailored to provide the optimum efficiencyand throughput to the facility by having a larger number of stations inunits where the processing step has a long duration and a smaller numberof stations in units which short processing steps (e.g. a small numberof stations in the sample isolation unit; a larger number of stations inthe cell expansion unit). Segregation of processing stations by functionenables the provision of the optimum environment (lighting, electricalpower and other services, temperature control etc.) required for theprocessing stations within a common unit. These characteristics of theunitised parallel processing facility provide a number of key advantagesover the shortcomings of conventional duplicated parallel operationswhere all processes for a single patient are carried out within aseparate room (e.g. redundant duplication of equipment, scalabilityrequiring additional space and equipment services).

Description of one possible illustrative embodiment of the scalable celltherapy processing facility is made with reference to FIG. 1 . Thefacility comprises a number of processing cells (UNIT 1 to UNIT N)wherein samples from Patient 1 [101] to Patient n [102] are processed inparallel in separate closed disposable containers within the facility tomaintain patient sample integrity and identity at all times. A sample S1[103] containing cells from Patient 1 [101] is collected in a uniquelyencoded disposable container and transferred to UNIT 1 [104] to beginprocessing. UNIT 1 [104] comprises a number of processing stations P1/1[105] to P1/n [111] suitable for performing the first step in the cellprocessing work flow. Patient sample S1 [103] is processed on processingstation P1/1 [105] using a uniquely encoded disposable processingcomponent 1 [106]. Other samples from Patient 2 to Patient n [102] areprocessed in parallel with sample n [110] from Patient n [102] processedon processing station P1/n [111] using a uniquely encoded disposableprocessing component 1 [106]. Following completion of processing in UNIT1, sample 1 [116] is moved in a closed container to the next processingunit, UNIT 2 [107] for the next stage of processing on processingstation P2/1 [108] using a uniquely encoded disposable processingcomponent 2 [109] suitable for the processing operation to be carriedout. Processing of samples continues in parallel through processingunits UNIT 3 [112] to UNIT N [113] in which the final stage ofprocessing is performed using a separate uniquely encoded disposableprocessing component for each processing stage and each patient sample.The fully processed therapy sample 1 [114] is transported in a uniquelyencoded disposable closed container for administration to Patient 1[101] from whom the starting sample [103] was taken. Other samples fromPatient 2 to Patient n are similarly processed in parallel through thefacility at all times being isolated in enclosed uniquely encodeddisposable containers with the fully processed therapy sample n [115]being administered to Patient n [102] from whom the starting sample[110] was taken.

The preceding description of one possible embodiment of the presentinvention is provided for illustrative purposes only. Those skilled inthe art will readily appreciate that other means of providing the keyrequired features of the present invention for a unitised parallelprocessing cell therapy facility are possible.

All components in the processing chain, including an identity braceletor other identification means worn by the patient, carry uniqueencoding. Suitable encoding means include but are not limited toencoding using tags in printed, magnetic or electronic form which may beread by light, electronic or magnetic means, such as barcodes, QR codes,RFIDs or transponders. It will be readily understood by those skilled inthe art that a variety of encoding means are suitable for use in themethod of the current invention. One suitable encoding means compriseslight activated micro-transponders, such as those from the PharmaSeqcompany described in WO2002037721, U.S. Pat. Nos. 5,981,166 and6,361,950, which are small (500×500×200 μm) low cost silicon deviceswhich store a unique 30 bit read-only identity code and emit the code asradio frequency signal when powered and interrogated with a lightemitting reader device. All processing components (sample collectiontube, cell purification components, cell culture and expansioncomponents etc.) are pre-registered in a facility component registrywhere each component's function and intended stage of use in theprocessing workflow is logged against the component's unique identifiercode. In the descriptions of embodiments described herein the term‘transponder’ is intended to encompass any means of encoding a uniquesample identity which may be read by suitable reading means.

At each stage in the therapy processing workflow the identifier code isread into a unique patient specific record in a central database. Thefirst entry in the database is the identity code from the patientbracelet. At sample collection (e.g. blood collection) the samplecollection component identity code is read and two actions are carriedout:

-   -   1. The sample collection component identity code is checked        against the component registry to confirm the correct component        is being used for that stage in processing and;    -   2. The sample collection component identity code is added as the        second entry to the custody chain of component identity codes in        the patient record.

Following sample collection the filled collection component istransferred to the next operation in the processing workflow to performa processing step using a processing component specific to that workflowstage and two actions are carried out:

-   -   1. The processing component identity code is checked against the        component registry to confirm the correct component is being        used for that stage in processing and;    -   2. The processing component identity code is added as the third        entry to the custody chain of component identity codes in the        patient record.

Processing of the patient sample continues through the necessaryoperations with each transfer of physical sample from component tocomponent being accompanied by the check and record actions 1 & 2 withthe processing components being added as the fourth to the nth entry inthe custody chain.

At the end of the processing workflow when the therapeutic material isready for administration to the patient the following actions arecarried out:

-   -   1. The identity codes of the component containing the        therapeutic material and the patient identity bracelet are both        read and;    -   2. The patient record data base custody chain of component        identity codes is checked stepwise to ensure that all component        identity codes track back to the same patient identity.

Further features of the custody chain include the ability to link allcomponent identity codes to electronic manufacturer's and/or supplier'sbatch records whereby scanning of the component appends electroniccopies of component batch record files to the patient record file toenable traceability of all components used in processing the patient'ssample. In addition all commercially supplied reagents (e.g. cell growthmedia) carry transponders on their containers with identity codes linkedto the manufacture's batch records allowing electronic copies ofrecords, certificates of analysis etc. to be appended to the patientrecord. To allow for the use of non-commercially supplied, bespoke orother special reagents or formulations which may be prepared within thefacility, additional encoded reagent containers are provided for fillingand storage of facility produced reagents (e.g. virus preparations fortransduction of CAR T-cells in cancer immunotherapy).

These principles are demonstrated in the following illustrativeembodiment by reference to FIG. 2 . The patient undergoing cell therapywears an identity bracelet [201] or other non-removable identifyingdevice comprising a unique readable transponder code [202]. Thetransponder code is read by a reader [203] connected to a centraldatabase and the code stored in the patient's individual database record[204]. At the first stage in the cell therapy process a sample, forexample of blood, is taken from the patient into a sample collectiontube or container [206] carrying a unique transponder code. Thetransponder code for the sample collection tube or container is read bythe reader [203] and the identity code for the filled tube or containerstored in the patient's database record [204]. The transponder code isalso used to check the component function by reading a componentregistry [205] containing component functions matched to componenttransponder numbers for all components in the cell processing workflow.To further process the sample collection tube or container containingthe patient's blood sample the sample collection container or tube [206]must be connected to the first component [207] in the processingworkflow. Prior to connection the transponder on the first component[207] is read by the reader [203] and checked against the componentregistry [205] to confirm if the component is the next correct componentin the processing sequence. If the component is correct the componenttransponder code is appended to the patient's database record [204]. Ifthe component is not correct the operator is notified to select thecorrect component. The sample is sequentially processed through eachstage in the workflow using processing components 2 [208], 3 [209], 4[210] through to processing component n [211] with the number ofcomponents determined by the complexity and steps in the workflow. Ateach stage in sample transfer between components the transponder codeson each component are read by the reader [203], checked against thecomponent registry [205] and recorded in the patient's database record[204]. When sample processing is complete and the therapeutic materialis present in the last processing component [211] ready foradministration to the patient the transponder code on the component[211] and on the patient identity bracelet [202] are read on the reader[203] and the identity numbers checked against the patient record in thedatabase record [204] to ensure that the transponder identity number forthe final component containing the therapeutic material [211] tracksback through the custody chain of successive transponder codes stored inthe database record [204] to the same patient identity bracelet [202]transponder code read at sample collection. Matching of all transpondercomponent identity codes in the patient database record [204] confirmsthat the sample and therapy relate to the same patient in the identitycustody chain and therapy can proceed by administration of the samplestored in the final processing container [211].

The described embodiment is provided for illustrative purposes only andthose skilled in the art will appreciate that other means of achievingan identity custody chain providing the key features of the inventionare possible.

A further key aspect of the present invention is means to achieve aphysical and identity custody chain which prevents contamination,cross-contamination or partial or whole loss of a patient sample byenvironmental exposure in a non-sterile environment or through operatorerror. All samples and processed materials are handled, processed andstored in closed disposable containers which are specific to each stageof the processing workflow and interface with each processing station inthe workflow. All such process components are joined by connection meanswhich prevent:

-   -   1. Cross contamination of patient samples by cross-mixing of        parallel processing sample workflows being performed in the same        processing unit.    -   2. Loss of patient sample or processed material through the        incorrect order of use of components.

To maintain the physical separation and identity of the processedpatient sample all connections between processing components 1 to N inthe processing workflow are made using connectors furnished with meansto prevent loss, mixing or cross-contamination of the sample integritythrough operator error. Such connectors are designed and operated to:

-   -   A. Allow only the correct sequence of processing components to        be used in processing the patient sample preventing loss of the        patient sample through use of incorrect components in sequential        steps of the processing workflow.    -   B. Allow only components linked to the patient identity to be        coupled together preventing mixing or cross-contamination of the        sample with another sample being processed through the facility        in parallel.    -   C. Maintain a record of the identity of the patient sample at        all stages in the workflow preventing mixing or        cross-contamination of the sample with another sample being        processed through the facility in parallel.    -   D. Prevent the re-use of components preventing mixing or        cross-contamination of the sample with another sample being        processed through the facility in parallel.

These principles are demonstrated in the following illustrativeembodiment by reference to FIG. 3 . Connectors providing sample physicaland identity integrity comprise a female [301] connector linked viatubing [302] to a first processing component and a male connector [303]linked via tubing [304] to a second processing component. The maleconnector [303] and the female connector [301] are designed so as toform a liquid- and air-tight junction between two components whencorrectly connected. The connectors are further provided with means toestablish a sterile connection when connectors are joined together in anon-sterile environment, such as that described in U.S. Pat. No.6,679,529. The male connector [303] carries blocking pins [305]orientated to fit into location holes [312 & 313] located in the frontface of the female connector [301]. The blocking pins are prevented fromentering the location holes [312 & 313] by metal blocking shields [314 &315] held in slots within the female connector [301] which preventcoupling of the connectors to form a junction between the processingcomponents. The male and female connectors carry identity transponders[306] encoding the individual identities of the processing componentsattached to each of the connectors. To form a join between theconnectors the male [303] and female [301] connectors are placed in areading device [309] comprising means to align the connectors and meansto read information from the identity transponders [306] carried on eachconnector. On activation of the reader [309] the identity codes of thetwo connectors are read and the device software performs a componentcompatibility match check [310] to determine whether the two connectorspresent in the device form a correct sequential component coupling forsample processing. Additional checking is performed by the reader [309]software to further ensure the physical separation and identity of thepatient sample, for example the identity codes from the transponders[306] are checked to ensure that the component being offered to receivethe patient sample at a step in the processing workflow is not a wastecomponent having been previously used. If the match checking operation[310] confirms the correct identity of the paired connectors a powersupply [311] is activated to energise electromagnets [307 & 308] heldwithin the reading device. Activation of the electro magnets pulls theblocking shields [314 & 315] outwards and away from the location holes[312 & 313] in the female connector to an open position [316 & 317]allowing the blocking pins [305] in the male connector to enter thelocation holes [312 & 313] in the female connector. The connectors arenow pushed together to provide a secure operating connection [318]between the processing components. Following correct connection thereader [309] additionally records the identity code of each connectorfrom the transponders [306] and sends the data to the patient samplerecord to provide a sample identity custody chain. If the match checkingoperation [310] detects that the two connectors do not have the correctidentities to form a correct sequential component coupling for sampleprocessing, power is not supplied to the electromagnets [307 & 308]preventing the coupling of the connectors. The reader software thenprompts the operator to select the correct components to form anoperable connection.

The described embodiment is provided for illustrative purposes only andthose skilled in the art will appreciate that other means of providingcomponent connection meeting the required principles of maintainingsample physical and identity integrity may be used. Such means includebut are not limited to alternative methods of component encoding such asbarcoding, and magnetic strip and RFID tagging to identify correctcomponents for connection. Alternative means for prevention ofconnection of incorrect sequential components include but are notlimited to providing a sequential series of unique connectors withvarying mirrored dispositions of pins and holes or grooves and ridgeswhich physically preclude the connection of mismatched connectors. Suchconnection means can be designed and disposed to ensure that the outputfrom a first component will connect only to the input of a secondcomponent, the output from the second component will connect only to theinput of a third component and so on for a series of N components withthe output of the N−1th component connecting only to the input of theNth component in the series. Additionally the connectors may be colourand or shape coded to aid in manual or automated selection of correctcomponents and connection pairings.

A further key aspect of the invention is the provision of processinginstructions to a processing station directly from, or in response to, aprocessing component connected to a processing station. Each processingcomponent comprises means to instruct a processing station on the typeof processing component and if applicable, the variant type of theprocessing component and to instruct a processing station on processingthe patient sample held within the processing component. A processingcomponent variant type may comprise a different size, capacity or otherfeature of the component which requires individual processinginstructions specific to that variant. Such individual processinginstructions may have variant specific instructions for reagent volumes,pressures, flow rates, incubation times etc. which are specific for theoptimum operation of that processing component variant. For example aprocessing component for performing cell isolation may be provided intwo variants for processing different volumes of blood; such variantswill require different reagent volumes and hence different processinginstructions. Similarly a processing component used for cell expansion,such as a disposable bioreactor for cell culture, may be provided indifferent sizes and culture capacities to allow the growth of differentnumbers of cells for use in therapy; such variants will utilisedifferent volumes of culture media and different processinginstructions.

Linking processing instructions to a processing component and providingsuch instructions to a processing platform operably connected to theprocessing component provides:

-   -   a) means to ensure that the instructions for processing a        patient sample within the processing component are correct for        that component, obviating risk of sample loss through use of        incorrect processing instructions.    -   b) means to ensure that variants of processing components        performing the same operation at a different scale are provided        with specific processing instructions necessary for the correct        processing.    -   c) means to remove operator errors by directly instructing        processing stations.    -   d) means to permit processing to be carried out in an automated        environment using robotic means to achieve the processing        workflow where each processing station in the workflow is        appropriately instructed to perform a processing operation on        receipt of a processing component.

These principles are demonstrated in the following illustrativeembodiments by reference to FIG. 4 . In a first further embodiment ofthe invention a processing component [402] is operably connected to aprocessing station [401] by connectors [406] to permit sample processingwherein the processing component comprises a transponder [403] carryinga unique identity code. The unique identity code is linked to a databasein a central instruction store [405] to specific processing instructionsfor the type and variant of processing component carrying thetransponder [403]. The identity code carried by the transponder [403] isread by a reader [404] connected to the processing station [401] andchecked to confirm that the processing component is of the correct typefor processing on the processing station [401]. On receipt of theidentity code the reader [404] retrieves processing instructions fromthe instruction store [405] by wired or wireless communication and thereceived instructions are passed to the processing station [401] topermit the correct operation of the processing station in processing thepatient sample contained in the processing component [402].

In a second further embodiment of the invention (FIG. 5 ) a processingcomponent [502] is operably connected to a processing station [501] byconnectors [505] to permit sample processing wherein the processingcomponent comprises a transponder [503] carrying a unique identity code.The processing component [502] additionally comprises a storedprocessing instruction set [504] specific to the type and variant of theprocessing component [502]. The identity code carried by the transponder[503] is read by a reader [505] connected to the processing station[501] and checked to confirm that the processing component is of thecorrect type for processing on the processing station [501]. Theprocessing instruction set [504] is also read by the reader [505] bywired or wireless means and the processing instructions passed to theprocessing station [501]. The processing instruction set [504] carriedby the component [502] may be stored and read by a variety of meansincluding, but not limited to, storage of processing instructions bybarcoding, QR coding, magnetic and solid state memory, and reading ofprocessing instructions by optical or electronic means. In a furthervariant identity coding and instruction storage may comprise a singledata store carried on each processing component.

In a further embodiment analytical means are used to ensure matching ofa patient sample and a therapeutic material derived from the sample toensure identity integrity is maintained through processing. The patientsample is subjected to a suitable chemical, biochemical or molecularanalysis and a first biomarker signature characteristic of the sample isstored on the patient's database record. Following processing of thesample the resulting therapeutic material is analysed using the sameanalytical method and a second biomarker signature is stored on thepatient's database record. Prior to administration of the therapeuticmaterial the first biomarker signature of the original patient sampleand the second signature of the therapeutic material are checked toverify a match between the two signatures confirming that the patientsample and the processed material are both derived from the samepatient.

Suitable analytical means include, but are not limited to, analysis ofproteins, RNA and DNA. Suitable means for deriving a signature ofprotein biomarkers include analysis of cellular proteins, including butnot limited to, HLA antigens and blood group proteins by flow cytometry,ELISA or western blotting. Suitable means for deriving a signature forRNA and/or DNA include, but are not limited to, PCR, RT-PCR, DNAsequencing, SNP analysis, RFLP analysis, genetic fingerprinting and DNAprofiling. Particularly suitable methods include those in standard usein forensic medicine which analyse DNA repeat sequences that are highlyvariable such as variable number tandem repeats (VNTR) and in particularshort tandem repeats (STR) which are so variable that unrelatedindividuals are extremely unlikely to have the same VNTR. Such means canbe used to unambiguously assign a patient identity to a processedtherapeutic material by matching the STR signature of the originalpatient sample and the therapeutic material.

While preferred illustrative embodiments of the present invention aredescribed, one skilled in the art will appreciate that the presentinvention can be practiced by other than the described embodiments,which are presented for purposes of illustration only and not by way oflimitation. The present invention is limited only by the claims thatfollow.

The present invention comprises a system for parallel processing of aplurality of biological samples comprising: a first processing unit (U1)comprising a plurality of processing stations (P1/1 to P1/n), whereinthe first processing unit (U1) is configured for processing in parallela plurality of cellular samples (S1 to Sn) on the processing stations(P1/1 to P1/n) to produce a first plurality of processed cellularsamples (S1/1 to Sn/1); second processing unit (U2) containing aplurality of processing stations (P2/1 to P2/n), wherein the said firstplurality of processed cellular samples (S1/1 to Sn/1) are configured tobe transferred to the second processing unit (U2) and processed inparallel to produce a second plurality of processed cellular samples(S1/2 to Sn/2); and wherein the system is configured to vary at leastone processing instruction between at least two of the processingstations (P1/1 to P1/n) of the first processing unit (U1) and/or vary atleast one processing instruction between at least two of the processingstations (P2/1 to P2/n) of the second processing unit (U2); and whereineach of the plurality of processing stations of the first processingunit (U1) and/or the second processing unit (U2) in which the at leastone processing instruction is varied is configured to carry out cellculture or cell expansion.

In one aspect, the system in configured to vary at least one processinginstruction between at least two of the processing stations (P1/1 toP1/n) of the first processing unit (U1) and vary at least one processinginstruction between at least two of the processing stations (P2/1 toP2/n) of the second processing unit (U2).

In another aspect, varying the at least one processing instructioncomprises varying at least one of reagent volume, pressure, flow rate,and incubation time.

In a further aspect, the system is configured to carry out cell cultureor cell expansion on the plurality cellular samples (S1 to Sn) on theprocessing stations (P1/1 to P1/n).

In one aspect, each of the cellular samples (S1 to Sn) is enclosed in acontainer.

In another aspect, the system is automated.

In a further aspect, at least one robotic arm is used to automate thesystem.

In one aspect, the system further comprises tubing configured fortransferring said first plurality of processed cellular samples (S1/1 toSn/1) to the second processing unit (U2) containing a plurality ofprocessing stations (P2/1 to P2/n).

In another aspect, the system is configured to carry out cell expansionon the plurality cellular samples (S1 to Sn) on the processing stations(P1/1 to P1/n).

In a further aspect provided herein is a method for parallel processingof a plurality of biological cellular samples using the system asdescribed herein, comprising i) transferring the plurality of cellularsamples (S1 to Sn) to the first processing unit (U1) comprising theplurality of processing stations (P1/1 to P1/n); ii) processing inparallel said plurality of cellular samples (S1 to Sn) on the processingstations (P1/1 to P1/n) to produce the first plurality of processedcellular samples (S1/1 to Sn/1); iii) transferring said first pluralityof processed cellular samples (S1/1 to Sn/1) to the second processingunit (U2) containing the plurality of processing stations (P2/1 toP2/n); and iv) processing in parallel each of said first plurality ofprocessed cellular samples (S1/1 to Sn/1) on a processing station (P2/1to P2/n) to produce the second plurality of processed cellular samples(S1/2 to Sn/2); wherein in step ii) the processing of the pluralitycellular samples (S1 to Sn) on the processing stations (P1/1 to P1/n) ofthe first processing unit (U1) comprises varying at least one processinginstruction between at least two of the processing stations (P1/1 toP1/n), and wherein processing of the plurality cellular samples (S1 toSn) on the processing stations (P1/1 to P1/n) comprises cell culturingor cell expanding.

In one aspect, varying the at least one processing instruction comprisesvarying at least one of reagent volume, pressure, flow rate, andincubation time.

In another aspect, processing of the plurality cellular samples (S1 toSn) on the processing stations (P1/1 to P1/n) comprises cell culturing.

In a further aspect, each of the cellular samples (S1 to Sn) is enclosedin container.

In one aspect, each of the cellular samples (S1 to Sn) is enclosed in acontainer.

In a further aspect, said method is an automated method.

In another aspect, at least one robotic arm is used to automate themethod.

In one aspect, said first plurality of processed cellular samples (S1/1to Sn/1) are transferred to the second processing unit (U2) containingthe plurality of processing stations (P2/1 to P2/n) via tubing.

The invention claimed is:
 1. A system for parallel processing of aplurality of biological cellular samples comprising: a first processingunit (U1) comprising a plurality of processing stations (P1/1 to P1/n),wherein the first processing unit (U1) is configured for processing inparallel a plurality of cellular samples (S1 to Sn) on the processingstations (P1/1 to P1/n) to produce a first plurality of processedcellular samples (S1/1 to Sn/1); a second processing unit (U2)containing a plurality of processing stations (P2/1 to P2/n), whereinthe said first plurality of processed cellular samples (S1/1 to Sn/1)are configured to be transferred to the second processing unit (U2) andprocessed in parallel to produce a second plurality of processedcellular samples (S1/2 to Sn/2); and wherein the system is configured tovary at least one processing instruction between at least two of theprocessing stations (P1/1 to P1/n) of the first processing unit (U1)and/or vary at least one processing instruction between at least two ofthe processing stations (P2/1 to P2/n) of the second processing unit(U2); and wherein each of the plurality of processing stations of thefirst processing unit (U1) and/or the second processing unit (U2) inwhich the at least one processing instruction is varied is configured tocarry out cell culture or cell expansion.
 2. The system according toclaim 1, wherein the system in configured to vary at least oneprocessing instruction between at least two of the processing stations(P1/1 to P1/n) of the first processing unit (U1) and vary at least oneprocessing instruction between at least two of the processing stations(P2/1 to P2/n) of the second processing unit (U2).
 3. The systemaccording to claim 1, wherein varying the at least one processinginstruction comprises varying at least one of reagent volume, pressure,flow rate, and incubation time.
 4. The system according to claim 1,wherein the system is configured to carry out cell culture or cellexpansion on the plurality cellular samples (S1 to Sn) on the processingstations (P1/1 to P1/n).
 5. The system according to claim 1, whereineach of the cellular samples (S1 to Sn) is enclosed in a container. 6.The system according to claim 1, wherein the system is automated.
 7. Thesystem according to claim 5, wherein at least one robotic arm is used toautomate the system.
 8. The system according to claim 1, wherein thesystem further comprises tubing configured for transferring said firstplurality of processed cellular samples (S1/1 to Sn/1) to the secondprocessing unit (U2) containing a plurality of processing stations (P2/1to P2/n).
 9. The system according to claim 1, wherein the system isconfigured to carry out cell expansion on the plurality of cellularsamples (S1 to Sn) on the processing stations (P1/1 to P1/n).
 10. Amethod for parallel processing of a plurality of biological cellularsamples using the system of claim 8, comprising: i) transferring theplurality of cellular samples (S1 to Sn) to the first processing unit(U1) comprising the plurality of processing stations (P1/1 to P1/n); ii)processing in parallel said plurality of cellular samples (S1 to Sn) onthe processing stations (P1/1 to P1/n) to produce the first plurality ofprocessed cellular samples (S1/1 to Sn/1); iii) transferring said firstplurality of processed cellular samples (S1/1 to Sn/1) to the secondprocessing unit (U2) containing the plurality of processing stations(P2/1 to P2/n); and iv) processing in parallel each of said firstplurality of processed cellular samples (S1/1 to Sn/1) on a processingstation (P2/1 to P2/n) to produce the second plurality of processedcellular samples (S1/2 to Sn/2); wherein in step ii) the processing ofthe plurality cellular samples (S1 to Sn) on the processing stations(P1/1 to P1/n) of the first processing unit (U1) comprises varying atleast one processing instruction between at least two of the processingstations (P1/1 to P1/n), and wherein processing of the pluralitycellular samples (S1 to Sn) on the processing stations (P1/1 to P1/n)comprises cell culturing or cell expanding.
 11. The method according toclaim 10, wherein varying the at least one processing instructioncomprises varying at least one of reagent volume, pressure, flow rate,and incubation time.
 12. The method according to claim 10, whereinprocessing of the plurality cellular samples (S1 to Sn) on theprocessing stations (P1/1 to P1/n) comprises cell culturing.
 13. Themethod according to claim 10, wherein each of the cellular samples (S1to Sn) is enclosed in a container.
 14. The method according to claim 10,wherein said method is an automated method.
 15. The method according toclaim 14, wherein at least one robotic arm is used to automate themethod.
 16. The method according to claim 10, wherein said firstplurality of processed cellular samples (S1/1 to Sn/1) are transferredto the second processing unit (U2) containing the plurality ofprocessing stations (P2/1 to P2/n) via tubing.